Antibacterial small molecules and methods for their synthesis

Abstract

The present invention relates generally to compounds providing antibacterial therapeutic agents and preparations, and related methods of using and making antibacterial compounds. Antibacterial compounds of the present invention include chalcone, alkylpyrimidine, aminopyrimidine and cyanopyridine compounds and derivatives thereof exhibiting minimum inhibitory concentrations (MIC) similar to or less than conventional antibacterial compounds in wide use.

1. A compound having antimicrobial activity which has the formula: 
       
         
           
           
               
               
           
         
         and salts, and esters thereof, 
         where: 
         M is 
       
       
         
           
           
               
               
           
         
          where R 11  is a C1-C6 alkyl group, or a —NRR′group and R 12  is a C1-C6 alkyl group, where R and R′ are independently selected from hydrogen, or a C1-C6 alkyl group; 
         at least one of R 1  or R 2  is selected from: 
         —O—(CH 2 ) n —CO—NH 2 , where n is an integer ranging from 1-6, or 
         at least one of R 1 -R 5  is selected from: 
       
       
         
           
           
               
               
           
         
         where p are integers ranging from 1 to 6, r and s are integers ranging from 1 to 100; 
         R aa  is selected from hydrogen, a C1-8 alkyl group, a C2-C8 alkenyl group, a C2-C8 alkynyl group, a C6-C13 aryl group, a C6-C13 aralkyl group, a C2-C8 ether group, a C2-C8 thither group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkenyl group, a C3-C10 heterocyclic group having 1-3 heteroatoms, or a C3-C13 heteroaromatic group having 1-3 heteroatoms, each of which groups are optionally substituted with one or more halogens, —OR, —SR a , C3-C3-alkyl, —COOH, —COO − , —NR a R′ a , —NR a R′ a R″ a , —CONR a R′ a , —NR a —C(NR a R′ a )═NR a , or —NR a —C(NR a R′ a )═NR a R′ a   +  groups, where R a , R′ a  and R″ a  are independently hydrogen or C1-C3 alkyl groups, 
         R b  is hydrogen, or a C1-C3 alkyl; or 
         R b  and R aa  together with the atoms to which they are attached form an optionally substituted C5-C8 heterocyclic ring having 1 or 2 heteroatoms; 
         R p  is selected from hydrogen, a C1-8 alkyl group, a C2-C8 alkenyl group, a C2-C8 alkynyl group, a C6-C13 aryl group, a C2-C8 ether group, a C2-C8 thioether group, a C3-C8 cycloalkyl group optionally having 1 or 2 heteroatoms, a C3-C8 cycloalkenyl group optionally having 1 or 2 heteroatoms, a C3 -C13 heteroaromatic group having 1-3 heteroatoms, all of which are optionally substituted with one or more of —OR c , —SR c , C1-C3-alkyl, —COOH, —COO − , —NR c R′ c , —NR c NR′ c R″ c , —CONR c R′ c , —N Rc —C(NR c R′ c )═NR c , and —NR c —C(NR c R′ c )═NR c R′ c   + , where R c , R′ c  and R″ c  are independently hydrogen or a C1-C3 alkyl group; 
         each R 13  and R 14  is independently selected from hydrogen; a C1-C6 alkyl group optionally substituted with one or more halogens; or a benzyl group or a phenyl group optionally substituted with one or more halogens, hydroxyl groups or C1-C3 alkyl groups or 
         one of R 13  or R 14  together with R p  and the atoms to which they are attached form an optionally substituted C4-C8 heterocyclic group which contains 1 or 2 heteroatoms and which optionally contains 1 or 2 double bonds; 
         the remaining R 1 -R 5  are selected from hydrogen, halogen, a hydroxyl group, a —NR d R′ d  group, a —CN group, an azide group, a —NO 2  group, an optionally substituted C1-C12 alkyl group, an optionally substituted C2-C12 alkenyl group, an optionally substituted C2-C12 alkynyl group, an optionally substituted C6-C13 aryl group, an optionally substituted C1-C12 alkoxy group, an optionally substituted C6-C13 aryloxy group, or an optionally substituted C3-C8 heterocycloalkyl group, and 
         R 6 -R 10  are independently selected from hydrogen, halogen, a hydroxyl group, a —NR d R′ d  group, a —CN group, an azide group, a —NO 2  group, an optionally substituted C1-C12 alkyl group, an optionally substituted C2-C12 alkenyl group, an optionally substituted C2-C12 alkynyl group, an optionally substituted C6-C13 aryl group, an optionally substituted C1-C12 alkoxy group, an optionally substituted C6-C13 aryloxy group, or a —O—(CH 2 ) m —CO—NH 2  group, where m is 1-6, 
         where R d , and R′ d  are selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C4-C8 heterocycloakyl and C6-C13 aryl, and 
         where optional substitution of R 1 -R 10  groups is substitution with one or more halogen, —OR e , —SR e , —COOH, —COO − , —NR e R′ e , —NR e R′ e R″ e , —CONR e R′ e , —NR e —C(NR e R′ e )═NR e , —NR e —C(NR e R′ e )═NR e R′ e   + , or C1-C3-alkyl group optionally substituted with one or more halogens,—OH, —SH, —COOH, —COO − , C1-C3 alkoxy groups, —NR e R′ e , or —CONR e R′ e , where R e , R′ e , and R″ e  are selected from hydrogen, a C1-C3 alkyl group, or a C6-C13 aryl group each of which is optionally substituted with one or more halogens, —OH, —SH, —COOH, —COO − , or C1-C3 alkoxy; provided that not every R 6 -R 10  is hydrogen. 
       
     
     
       2. A compound of  claim 1 , wherein R 1  or R 2  is a —O—(CH 2 ) n —CO—NH 2  group, where n is 1-6 and the remaining R 1 -R 5  are independently selected from hydrogen, halogen, a hydroxyl group, a —NR d R′ d  group, a —CN group, an azide group, a —NO 2  group, an optionally substituted C1-C12 alkyl group, an optionally substituted C2-C12 alkenyl group, an optionally substituted C2-C12 alkynyl group, an optionally substituted C6-C13 aryl group, an optionally substituted C1-C12 alkoxy group, an optionally substituted C6-C13 aryloxy group, or an optionally substituted C3-C8 heterocycloalkyl group. 
     
     
       3. A compound of  claim 2  where R 11  is a methyl group or a —NH 2  group and R 12  is a methyl group. 
     
     
       4. A compound of  claim 2 , wherein R 1  is a —O—(CH 2 ) n —CO—NH 2  group, where n is 1-6. 
     
     
       5. A compound of  claim 1  having formula: 
       
         
           
           
               
               
           
         
         and salts, and esters thereof. 
       
     
     
       6. A compound of  claim 5 , wherein R 1  or R 2  is a —O—(CH 2 ) n —CO—NH 2  group, where n is 1-6 and the remaining R 1 -R 5  are independently selected from hydrogen, halogen, a hydroxyl group, a —NR d R′ d  group, a —CN group, an azide group, a —NO 2  group, an optionally substituted C1-C12 alkyl group, an optionally substituted C2-C12 alkenyl group, an optionally substituted C2-C12 alkynyl group, an optionally substituted C6-C13 aryl group, an optionally substituted C1-C12 alkoxy group, an optionally substituted C6-C13 aryloxy group, or an optionally substituted C3-C8 heterocycloalkyl group. 
     
     
       7. A compound of  claim 6  wherein R 2  is a —O—(CH 2 ) n —CO—NH 2  group, where n is 1-6 and R 1 , and R 3 -R 5  are hydrogens. 
     
     
       8. A compound of  claim 7  wherein R 6 -R 10  are selected from hydrogen, a chlorine, a bromine, or a trifluoromethyl group. 
     
     
       9. A compound of  claim 6 , wherein R 1  is a —O—(CH 2 ) n —CO—NH 2  group, where n is 1-6, R 4  is hydrogen, a chlorine or a bromine, and R 2 , R 3  and R 5  are hydrogens. 
     
     
       10. A compound of  claim 9  wherein R 6 -R 10  are selected from hydrogen, halogen, a C1-C3 alkyl group, a C1-C3 haloalkyl group, a C1-C3 alkoxy group, a phenyl group, or a phenoxy group. 
     
     
       11. A compound of  claim 9  wherein R 6 -R 10  are selected from hydrogen, a chlorine, a bromine, or a trifluoromethyl group. 
     
     
       12. A compound of  claim 6  wherein R 1  or R 2  is a —O—(CH 2 ) n —CO—NH 2  group, where n is 1-6, R 4  is a halogen and at least one of R 6 -R 10  is a halogen or a halogenated alkyl group. 
     
     
       13. A compound of  claim 6  wherein R 1  is a —O—(CH 2 ) n —CO—NH 2  group, where n is 1-6, and at least one of R 6 -R 10  is a halogen or a halogenated alkyl group. 
     
     
       14. A compound of  claim 13  wherein at least R 7  and R 9  are halogens or halogenated alkyl groups. 
     
     
       15. A compound of  claim 14  wherein R 4  is hydrogen, a halogen, a —CN group, an azide group, a —NO 2  group, a C1-C3 alkyl group or a halogenated C1-C3 alkyl group. 
     
     
       16. A compound of  claim 15  wherein R 4  is hydrogen, a bromine or a chlorine. 
     
     
       17. A compound of  claim 14  wherein both of R 7  and R 9  are halogens or halogenated alkyl groups and R 6 , R 8  and R 10  are selected from hydrogen or C1-C3 alkyl groups. 
     
     
       18. A compound of  claim 17  wherein R 4  is hydrogen, a halogen, a —CN group, an azide group, a —NO 2  group, or a halogenated C1-C3 alkyl group. 
     
     
       19. A compound of  claim 18  wherein R 4  is hydrogen, a bromine or a chlorine. 
     
     
       20. The compound of  claim 1  selected from: 
       
         
           
           
               
               
           
         
       
       or salts or esters thereof. 
     
     
       21. A compound of  claim 1  having formula: 
       
         
           
           
               
               
           
         
       
       and salts, and esters thereof wherein R 1  is selected from:
 a —O—(CH 2 ) n —CO—NH 2  group, where n is 1-6; 
 
       
         
           
           
               
               
           
         
         R 7  and R 9  are halogens or halogenated alkyl groups. 
       
     
     
       22. A compound of  claim 21  wherein R 4  is hydrogen, a halogen, a —CN group, an azide group, a —NO 2  group, a C1-C3 alkyl group or a halogenated C1-C3 alkyl group. 
     
     
       23. A compound of  claim 21  wherein R 4  is hydrogen, a bromine or a chlorine. 
     
     
       24. A compound of  claim 21  wherein R 6 , R 8  and R 10  are selected from hydrogen or C1-C3 alkyl groups. 
     
     
       25. A compound of  claim 21  wherein R 4  is a hydrogen or a halogen; R 2 , R 3 , and R 5  are hydrogens; R 7  and R 9  are independently halogens or halogenated alkyl groups, R 6  is a halogen or hydrogen, and R 8  and R 10  are hydrogens. 
     
     
       26. A compound of  claim 21  wherein R 4  is a hydrogen, chlorine or bromine; R 2 , R 3 , and R 5  are hydrogens; R 7  and R 9  are independently chlorine bromine or trifluoromethyl groups, R 6  is a chlorine, bromine or hydrogen, and R 8  and R 10  are hydrogens. 
     
     
       27. A compound of the formula selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or salts and esters thereof. 
     
     
       28. A pharmaceutical composition which comprises a compound of  claim 1  in a therapeutically effective amount for inhibition of an infectious agent and a pharmaceutically acceptable carrier. 
     
     
       29. A method of treating a bacterial infection in a subject comprising the step of administering a therapeutically effective amount of a compound of  claim 1  or a pharmaceutical formulation thereof to said subject in need thereof. 
     
     
       30. A method of inhibiting growth of a microorganism comprising the step of contacting said microorganism with an effective amount of a compound of  claim 1  or a pharmaceutical formulation thereof, wherein said microorganism is a bacteria. 
     
     
       31. The method of  claim 30  wherein said bacteria are Gram-positive bacteria. 
     
     
       32. The method of  claim 30  wherein said bacteria are selected from the group consisting of  Bacillus, Listeria, Staphylococcus, Streptococcus, Enterococcus, Corynebacterium, Propionibacterium  and  Clostridium.    
     
     
       33. The method of  claim 30  wherein said bacteria are selected from the group consisting of:  S. aureus, S. epidermidis , and  B. subtilis.